Mavacamten depresses human atrial contractility in the same EC50% range as human ventricle

In obstructive HCM patients, recent phase III placebo-controlled randomized EXPLORERHCM clinical trial demonstrated the efficacy and safety of Mavacamten in reducing left ventricular (LV) outflow tract gradient and ameliorating exercise capacity (Olivotto et al. 2021). Both effects are attributable to a local reduction of LV septal contractility. Although very promising, this class of small molecules can globally depress cardiac muscle contractility with potential detrimental consequences on the overall cardiac output. Here we characterized the effect of Mavacamten on the contractile properties of human atrial myocardium (from surgical samples), expressing different levels of α and β myosin isoforms. In intact trabeculae Mavacamten (0.5-5.0 µM) reduced the amplitude of atrial twitches in a dose dependent manner with a variable effect on twitch duration, ranging from no effect in atrial myocardium expressing >95% α myosin to a mild acceleration of peak and relaxation times in atrial myocardium with a 50:50% α:β myosin ratio. In human atrial myofibrils expressing >95% α myosin (15°C), Mavacamten had a fast, fully reversible, and dose-dependent negative effect on Ca2+-activated isometric force, with an EC50% close to that of human ventricular myofibrils expressing 100% β-myosin. Importantly, at variance with what reported in ventricular myofibrils (Scellini et al 2021), Mavacamten strongly depressed the kinetics of force generation of human α-myosin atrial myofibrils similarly to what had been observed in fast skeletal muscle myofibrils. In summary, Mavacamten reduced atrial twitch amplitude with variable impact on twitch kinetics, likely related to different α:β myosin ratios and to the different impact of the drug on the fast and slow myosin isoforms. As in obstructive HCM ventricular filling strongly relies on atrial contraction, depressing atrial contractility with Mavacamten could detrimentally reduce ventricular systolic function.